The present invention relates to the preparation of 2-deoxy-2,2-difluoro-.beta.-D-ribo-pentopyranose (III) from 3,3-difluoro-4,5,6-trihydroxy-5,6-O-(1-ethylpropylidene)hexene (I), wherein a pentopyranose isomer (IIIA) is produced preferentially. The hexene (I) is prepared by a novel process from glyceraldehyde pentanide. The pentopyranose isomer (IIIA) is an intermediate to 2'-deoxy-2',2'-difluorocytidine, a known antiviral agent.
Hanzawa, et al., Tetrahedron Letters, 28, 659-662 (1987) describe the reaction of bromodifluoromethylacetylene compounds with various aldehydes. The reaction was conducted at 0.degree. C. and mercurous chloride was necessary to activate the zinc. There was no need for a protective atmosphere. The yields of the acetylenic difluoro acetonides were in the 50 to 78% range. A 2,2-difluoro ribose was produced from an intermediate difluoro acetonide using a complex series of reactions. There is no indication of any preference for any isomeric product.
Yang, et al., J. Organic Chem., 56, 1037-1041 (1991) describe the general preparation of .alpha.,.alpha.-difluorohomoallylic alcohols by the reaction of an aldehyde, zinc and 3-bromo-3,3-difluoropropene. None of the reactions involved protected glyceraldehydes or other chiral aldehydes so there is no indication of any isomeric preference. The reference does show that various metals can be used to form the complex, particularly cadmium and tin. Seyferth, et al., J. Am. Chem., 105, 4634-4639 (1983) shows the use of a lithium complex in general reactions with an aidehyde, but not with protected glyceraldehydes or chiral aldehydes. There is no showing of preferential production of an isomer. Hertel, et al., J. Org. Chem., 53, 2406-2409 (1988) disclose the preparation of pentopyranose isomer (IIIA) from difluoroacetates, while Nagarajan's patent (U.S. Pat. No. 4,954,623) produces it by degrading a nucleoside. Importantly, however, Nagarajan's patent also discloses use of difluorodeoxyribose IIIA to prepare the ribofurano-1,4-lactone intermediate which is used in the Hertel and Chou papers (Chou, et al., Synthesis, 565-570 (1992)) to prepare 2'-deoxy-2',2'-difluorocytidine. In the Hertel and Nagarajan preparations of IIIA, its xylo isomer IIIB is not present and therefore separation of the two isomers is not shown. Hanzawa, et al., Tet. Lett., 28, 659-662 (1987) show a general reaction to produce a difluorodeoxyribose which was not suitable for nucleoside formation. Triacetoxydifluoro-deoxy pyranosylribose was isolated, not the unprotected form needed to form 2'-deoxy-2',2'-difluorocytidine.
It is therefore an object of the present invention to provide a novel process for the preparation of a ribo-pentopyranose intermediate to the preparation of 2'-deoxy-2',2'-difluorocytidine. Further, it is an object of the present invention to provide a novel reaction to produce 3,3-difluoro-4,5,6-trihydroxy-5,6-O-(1-ethylpropylidene)hexene (I), particularly with a significant excess of the erythro isomer. These and other objects will become increasingly apparent by reference to the following description.